Worse Survival Prognosis Research Articles

Comparative analysis of first-line treatment in NSCLC including unresectable stage III (IIIB/IIIC) and stage IV with low PD-L1 expression: Clinical trial eligible versus ineligible patients.

Clinical trial eligible patients with advanced non-small cell lung cancer (aNSCLC) and low programmed cell death ligand 1 (PD-L1) expression achieve greater benefit from immune checkpoint inhibitor (ICI) combination chemotherapy (ICI-Chemo) compared with Chemo alone. We examined whether patients ineligible for clinical trials may benefit from ICI-Chemo. This multicenter retrospective cohort study enrolled patients with aNSCLC, including unresectable Stage III (IIIB/IIIC) and IV disease with a PD-L1 tumor proportion score of 1-49% treated with ICI-Chemo or Chemo as first-line therapy from 2018 to 2023 in Japan. Treatment outcome and safety of ICI-Chemo versus Chemo groups in trial-eligible and trial-ineligible patients was compared based on criteria from previous phase III clinical trials. Overall, 728 patients were analyzed: 333 trial-eligible and 395 ineligible patients. The median overall survival was 25.1months in the ICI-Chemo group and 18.5months in the Chemo group for eligible patients (HR 0.73, 95%CI: 0.54-0.97) and was 18.2months in the ICI-Chemo group and 14.9months in the Chemo group for ineligible patients (HR 0.75, 95%CI: 0.59-0.95). Median progression-free survival was longer with ICI-Chemo in both groups. For ineligible patients, performance status (PS)≥2 and squamous cell carcinoma (SqCC) were clinical factors associated with worse survival prognosis, and survival outcomes with ICI-Chemo and Chemo were comparable. The ineligible group had no increase in severe adverse events compared to the eligible group. This study suggests a possible clinical benefit of receiving ICI-Chemo for trial-ineligible patients with low PD-L1 expression, excluding those with PS ≥2 or SqCC.

PIM1 Point Mutations Increase Migration of Diffuse Large B-Cell Lymphoma (DLBCL) Cells

PIM1 serine-threonine kinase is known proto-oncogene, highly expressed in lymphoid malignancies. It regulates crucial processes for the cancer cell, like proliferation, apoptosis, metabolism or migration. In DLBCLs, PIM1 gene is a target of somatic hypermutation and one of the most frequently mutated genes in DLBCL patients. PIM1 mutations are more frequent in ABC-type tumors, which have worse survival prognosis than GCB-type, and often co-occur with mutations in MYD88 and CD79B. Analyses of the available clinical data show that the most significant differences between the groups of DLBCL patients with or without PIM1 mutations are tumor mutational burden, age at diagnosis and extranodal (testicular) involvement. In line with this finding, PIM1, MYD88 and CD79B mutations have also been reported to be highly prevalent in extranodal B cell lymphomas, localized in central nervous system (PCNSL), testicles (PTL) or intravascular space (IVLBCL). Our goal was to assess the role of the most common PIM1 point mutations in the biology and pathogenesis of DLBCL cells. The HBL-1 cell line was chosen as a model of MYD88 L265P-positive ABC-DLBCL subtype. PIM1 knock-out was performed using CRISPR/Cas9 method. Sequences of wild type PIM1, kinase-dead PIM1K67M, serving as a an inactive kinase control, and 7 most frequent mutants (PIM1G28D, PIM1E70K, PIM1P81L, PIM1S97N, PIM1P125A, PIM1L164F, PIM1L184F) were reintroduced to the HBL-1 PIM1 KO cells using lentiviral vectors. PIM1 mutations did not affect the proliferation of DLBCL cells and did not increase resistance to doxorubicin, excluding the proliferation rate or treatment resistance as a cause of the poor prognosis associated with PIM1 mutations. We performed RNA-seq analysis of the HBL-1-PIM1-WT and HBL-1-PIM1-mutants. The most upregulated pathways in PIM1 mutants (including PIM1K67M) were those related to Interferon gamma, IL-15, STAT3, cMET and semaphorin-plexin signaling (involved in proliferation, actin dynamics and migration of cancer cells). We also found that PIM1 mutants universally overexpress cMET oncogene. Moreover, gene set and pathway enrichment analyses indicated that the PIM1-mutant cells exhibit features associated with altered actin polymerization, RHO GTPases and cell membrane dynamics, suggesting the increased migratory potential of the cells and their propensity to spread to extranodal sites. Higher surface level of cMET in PIM1 mutant cells was confirmed using FACS analysis. Since cMET and CXCR4 cooperate in signaling and trigger AKT/mTOR, which is required for CXCR4-mediated cell motility, we evaluated whether PIM1 mutant cells would exhibit increased phosphorylation of AKT. In line with this hypothesis, we noted higher pAKT and pERK1/2 in PIM1 mutant cells than in PIM1 WT cells. Finally, in transwell assays, PIM1 mutant cells exhibited markedly increased migratory potential. Taken together, these studies indicate that PIM1 mutants are not likely associated with differential drug responses, but rather facilitate tumor dissemination and are thus associated with inferior prognosis in DLBCL patients harboring PIM1 mutations.

Selinexor in Combination with Azacitidine (AZA) in Patients with Myelodysplastic Syndrome (MDS): A Real-World Retrospective Study

Background: Patients with higher-risk MDS face limited treatment options and poor outcomes. While HMAs are approved as frontline therapy for higher-risk MDS, primary failure occurs in 50% of HMA-treated patients, and most responders progress within 2 years. There is an unmet need to improve the efficacy of AZA frontline therapy while maintaining a tolerable safety profile. Preclinical studies have demonstrated that the combination of selinexor and azacitidine synergistically inhibits MDS cell proliferation and arrests the cell cycle at the G2/M phase (Yixuan Guo, 2022). The combination of selinexor and azacitidine may be a promising approach for treating MDS. Here, we present this single-center, real-world evidence supporting the use of selinexor in combination with AZA in MDS patients. Methods: Medical records of 19 patients with MDS receiving selinexor in combination with AZA at the First Affiliated Hospital of Soochow University between Jan 2022 and March 2023 were reviewed. Inclusion criteria were a pathologically confirmed diagnosis of MDS, and receipt of ≥1 cycle of azacitidine in combination with selinexor. HMA-naïve patients and those previously treated with HMAs were included. Patients with a diagnosis other than MDS or progression to AML before treatment with selinexor + AZA were excluded. Patients received selinexor 40-60 mg QW orally and AZA 75 mg/m 2 intravenously or subcutaneously on days 1-5 or 7 of each 28-day cycle. Responses were evaluated per the International Working Group criteria. Results: A total of 19 pts (median age, 54 y [range, 13-68 y]) were treated (Table 1). IPSS-R risk was high or very high in 15.8% and 68.4% of pts, respectively. IPSS-M risk was high or very high in 10.5% and 78.9% of pts, respectively. 57.9% of pts were previously treated with HMA. 63.2% had myelofibrosis, 42.1% had hepatosplenomegaly, 31.6% had a TP53 mutation, and 63.2% had poor or very poor-risk cytogenetics. As of Jun 10, 2023 at a median follow-up of 5.9 months (range 1.5-17.4 months), eight pts died (42.1%) due to disease progression. For the total cohort, the overall response rate (ORR) was 73%. In pts with worse survival prognosis, such as relapse and refractory, high and very high in IPSS-R, high and very high in IPSS-M, myelofibrosis and TP53 mut, the ORR was 64%, 81%, 76%, 75% and 83%, respectively (Figure 1). In seven pts with splenomegaly, six pts had reduced spleen volume, and one pt had no significant change by abdominal palpation or imaging examination. The 6-month overall survival (OS) was 74.7% in total pts, and 70.0% in pts previously exposed to HMA (Figure 2a, 2b). Selinexor + AZA therapy improved survival of patients with poor prognosis, such as TP53 mut (0.099), MF (+) (0.613), ≥high in IPSS-R (0.938) (Figure 2c, 2d, 2e). The survival of six pts who received transplantation after combination therapy was significantly prolonged, with 6-month OS was 83.3% (Figure 2f). Conclusion: Selinexor + AZA combination therapy was well tolerated with promising efficacy in patients with untreated or relapse/refractory MDS, including those with TP53 mutation, myelofibrosis, and higher risk in IPSS-R.

Upregulated enhancer of rudimentary homolog promotes epithelial‑mesenchymal transition and cancer cell migration in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the deadliest cancers regarding both mortality rate and number of deaths and warrants greater effort in the development of potential therapeutic targets. The enhancer of rudimentary homolog (ERH) has been implicated in the promotion and progression of certain types of cancer. In the present study, ERH was assessed for its expression pattern and survival association with LUAD in public transcriptomic and proteomic databases. Bioinformatic methods and data from websites, including University of Alabama at Birmingham CANcer data analysis Portal and The Cancer Genome Atlas, were utilized to demonstrate the functional behaviors and corresponding pathways of ERH in LUAD. Human A549 and CL1‑0 cell lines were used to validate the findings via functional assays. It was demonstrated that the expression of ERH, at both the transcriptomic and proteomic levels, was higher in LUAD compared with in adjacent non‑tumor lung tissue and was associated with worse survival prognosis. Moreover, high ERH expression was correlated with more aggressive functional states, such as cell cycle and invasion in LUAD, and the positive ERH‑correlated gene set was associated with worse survival and an immunosuppressive tumor microenvironment. Small nuclear ribonucleoprotein polypeptide G was identified as a molecule that potentially interacted with ERH. Lastly, it was demonstrated that ERH promoted epithelial‑mesenchymal transition and cell migration invitro, but not proliferation. In conclusion, higher expression of ERH in LUAD may facilitate cancer progression and confer worse outcomes. Further deep investigation into the role of ERH in LUAD is needed.

Circ-PGPEP1 augments renal cell carcinoma proliferation, Warburg effect, and distant metastasis.

Circular RNAs (circRNAs) contribute to the malignant phenotype and progression of several types of human cancers, including renal cell carcinoma (RCC). This study probed the molecular mechanism of circPGPEP1 regulating RCC proliferation, Warburg effect, and distant metastasis by targeting the miR-378a-3p/JPT1 axis. Here identified higher circPGPEP1 expression in RCC tissues and cells by RT-qPCR, and high levels of circPGPEP1 were positively correlated with high histological grade and distant metastasis in RCC patients. Furthermore, patients with high levels of circPGPEP1 had a worse survival prognosis. Functional assays presented that knockdown of circPGPEP1 inhibited RCC proliferation, invasion, migration, EMT, and Warburg effect. Dual-luciferase reporter assay, RNA immunoprecipitation, nucleoplasmic RNA isolation, and functional rescue experiments confirmed that circPGPEP1 induced JPT1 expression by sponging miR-378a-3p, thereby promoting RCC malignant phenotype. Xenograft assays and metastasis models further demonstrated that down-regulation of circPGPEP1 effectively inhibited tumor growth and distant metastasis of RCC. Taken together, circPGPEP1, a prognostic circRNA in RCC, acts through the miR-378a-3p/JPT1 axis to regulate RCC progression.

COX2-Inhibitory and Cytotoxic Activities of Phytoconstituents of Matricaria chamomilla L.

Chamomile tea is a popular beverage and herbal remedy with various health benefits, including antioxidant and antimicrobial activities and beneficial effects on metabolism. In this study, we investigated the inhibitory activities of secondary metabolites from Matricaria chamomile L. against COX2, an enzyme involved in inflammation and linked to cancer development. The cytotoxicity of the compounds was also evaluated on a panel of 60 cancer cell lines. Myricetin, one of the COX2-inhibiting and cytotoxic compounds in chamomile tea, was further studied to determine a proteomic expression profile that predicts the sensitivity or resistance of tumor cell lines to this compound. The expression of classical mechanisms of anticancer drug resistance did not affect the responsiveness of cancer cells to myricetin, e.g., ATP-binding cassette (ABC) transporters (ABCB, ABCB5, ABCC1, ABCG2), tumor suppressors (p53, WT1), and oncogenes (EGFR, RAS), whereas significant correlations between myricetin responsiveness and GSTP expression and cellular proliferation rates were observed. Additionally, Kaplan–Meier survival time analyses revealed that high COX2 expression is associated with a worse survival prognosis in renal clear cell carcinoma patients, suggesting a potential utility for COX2 inhibition by myricetin in this tumor type. Overall, this study provides insight into the molecular modes of action of chamomile secondary metabolites and their potential as cancer-preventive or therapeutic agents.

Effect of baseline cancer pain on the efficacy of immunotherapy in lung cancer patients.

Cancer pain is a common symptom in cancer patients. However, few reports have evaluated the effect of baseline cancer pain on the efficacy of immunotherapy in lung cancer patients. The aim of this retrospective study is to reveal the effect of baseline cancer pain on the prognosis of lung cancer patients receiving immunotherapy. We retrospectively reviewed the medical records of lung cancer patients who received immunotherapy at Zhejiang Cancer Hospital and were included 280 patients with or without baseline cancer pain. Propensity score matching (PSM) was used to minimize potential selection bias. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier estimation and log-rank tests. Cox proportional hazard regression analysis was performed to identify factors associated with survival independence. The median PFS and OS of the patients with baseline cancer pain were significantly shorter than that of patients without baseline cancer pain (PFS: 3.1 vs. 6.5 months, P=0.001; OS: 16.5 vs. 31.2 months, P<0.001). PSM also included 27 patients with or without breakthrough pain. Patients with breakthrough pain had significantly shorter median PFS and OS than those without breakthrough pain (PFS: 1.9 vs. 4.2 months, P=0.001; OS: 9.9 vs. 18.7 months, P=0.012). Cox analysis results implicated breakthrough pain as an independent prognostic factor for immunotherapy. Baseline cancer pain is a negative prognostic factor for lung cancer patients receiving immunotherapy. Patients with baseline cancer pain may have a worse survival prognosis if they develop breakthrough pain.

Bisphenol A increases the size of primary mammary tumors and promotes metastasis in a murine model of breast cancer

Triple negative breast cancer (TNBC) is a subtype of breast tumor characterized for the absence of estrogen and progesterone receptors expression and low HER2/neu expression. Bisphenol A (BPA) is an endocrine disrupting chemical with estrogenic activity that has been associated with increasing rates of breast cancer. Moreover, BPA is a solid organic synthetic chemical employed in the manufacture of many consumer products, epoxy resins and polycarbonate plastics including baby bottles, containers for food and beverages, and the lining of beverage cans. The G-protein-coupled estrogen receptor (GPER) is activated by endogenous hormones and synthetic ligands, such as BPA. GPER is expressed in TNBC cells and its expression is associated with larger tumor size, metastasis and worse survival prognosis. In breast cancer cells, BPA induces activation of signal transduction pathways that mediates migration and invasion via GPER in human TNBC MDA-MB-231 cells. In this study, we demonstrate that BPA induces an increase of GPER expression and its translocation from cytosol to cytoplasmic membrane, metalloproteinase (MMP)-2 and MMP-9 secretion, migration and invasion in murine TNBC 4T1 cells. In a murine TNBC model “in vivo” using 4T1 cells, BPA induces the formation of mammary tumors with more weight and volume, and an increase in the number of mice with metastasis to lung and nodules in lung compared with tumors and metastasis to lung of untreated Balb/cJ mice. In conclusion, our findings demonstrate that BPA mediates the growth of mammary primary tumors and metastasis to lung in a murine model of breast cancer.

Prognostic value of soluble programmed cell death ligand-1 (sPD-L1) in lymphoma: a systematic review and meta-analysis.

Previous studies on the prognostic value of soluble programmed cell death ligand 1 (sPD-L1) in lymphoma patients have yielded inconsistent results. Here, we conducted a meta-analysis and systematic review to investigate the prognostic significance of sPD-L1 in lymphoma, especially in diffuse large B-cell lymphoma (DLBCL) and NK/T-cell lymphoma (NK/TCL). A total of 11 studies with 1185 patients were included in the meta-analysis, and the combined results indicated that high sPD-L1 levels were associated with worse overall survival (OS) (HR=2.27, 95%CI: 1.70-3.04) and progression-free survival (PFS) (HR=2.68, 95%CI: 1.92-3.75). Furthermore, subgroup analysis showed that sPD-L1 remained a significant prognostic factor for OS. The meta-analysis indicated that sPD-L1 may be a potential prognostic biomarker for lymphoma, especially in DLBCL and NK/TCL, and high sPD-L1 levels were associated with worse survival prognosis.

A review of the research on the cardiovascular risk factors and treatment options for Type II diabetic patients

The rise in the prevalence of diabetes is attributed to changes in human behavior, environment, and lifestyle. The prolonged survival of diabetes patients has been made possible by better care, but this is accompanied by chronic long-term problems brought on by hyperglycemia. Diabetes-related conditions like ketoacidosis or hypoglycemia are fewer common causes of death for diabetics than cardiovascular disease (CVD). Cardiovascular disease is more common in diabetes patients by a factor of 2 to 6 compared to the general population. Additionally, diabetics with CVD have a worse prognosis for survival than those with CVD who don't have diabetes, and their quality of life also declines. As a result, diabetes has been compared to a non-diabetic patient who has a history of heart disease in terms of risk. Identifying patients with a high risk of developing CVD can help prevent or delay cardiovascular events. Chemists must closely monitor these issues to manage CVD prevention and related ones. Patients taking aspirin and clopidogrel for an extended period should be constantly monitored due to the possibility of resistance. Guidelines have been developed to monitor and manage aspirin and clopidogrel in CVD preventive therapy.

Morphological features of epithelial-mesenchymal transformation and its effect on tumor progression of breast cancer

Introduction. Breast cancer is in the first place in the structure of morbidity among all malignant neoplasms in women. The prognosis of the disease depends on the tumor degree, including the presence of epithelial-mesenchymal transformation (EMT), the degree of invasion, the proliferative index, the preservation or absence of estrogen, progesterone, and epidermal growth factor receptors.Aim: To study the immunohistochemical and morphological characteristics of the epithelial-mesenchymal transformation of breast cancer.Material and Methods. Immunohistochemical study with antibodies to AE1/AE3, HMW, CK18, Snail, HER2/neu, E-cadherin, Vimentin, α-SMA, CD34, Ki-67 and p63 was performed in 60 patients of different age with breast cancer. Native preparations were stained with picrofuchsin according to van Gieson Alcian blue. Inflammatory infiltrate cells were examined for antibodies CD45, CD3, CD4, CD8, CD20, CD68.Results. In ductal carcinoma, positive expression for estrogen and progesterone was found in 82.7% and 86.3%, respectively, the proliferation index ranged before 66,6%, and p-53 was positive in 97%. In lobular cancer, positive expression to estrogen and progesterone was observed in 83.4% and 66.6%, respectively, the index of proliferative activity at the level of 50%, and p-53 was positive in 66.6%. Positive moderate expression of HER-2/neu was determined in 47% of ductal and 50% of lobular cancers. Estrogen plays an important role in the development of invasive breast cancer, leads to tumor progression and contributes to EMT. EMT, in turn, leads to the expression of E-cadherin associated with a worse survival prognosis. EMT indirectly leads to the intensification of angiogenesis, and the presence of a large number of newly formed vessels increases the risk of metastasis. Histochemical methods were used to determine the growth of fibrous tissue around invasively growing cancer complexes. Cells located perifocally looked like fibrobla ts, immunohistochemically moderately expressed Vimentin and weakly expressed pancytokeratin, which proved the tumor nature of the cells and the acquisition of mesenchymal features by them. The inflammatory infiltrate along the periphery of the tumor growth consisted mainly of T- and B-lymphocytes, and around the cancer complexes - of B-lymphocytes and macrophages.Conclusion. The study of the immunohistochemical tumor phenotype will make it possible to prescribe adequate polychemotherapy and determine the prognosis of the course of the disease.

Morphological features of epithelial-mesenchymal transformation and its effect on tumor progression of breast cancer

Introduction. Breast cancer is in the first place in the structure of morbidity among all malignant neoplasms in women. The prognosis of the disease depends on the tumor degree, including the presence of epithelial-mesenchymal transformation (EMT), the degree of invasion, the proliferative index, the preservation or absence of estrogen, progesterone, and epidermal growth factor receptors.Aim. To study the immunohistochemical and morphological characteristics of the epithelial-mesenchymal transformation of breast cancer.Material and Methods. Immunohistochemical study with antibodies to AE1/AE3, HMW, CK18, Snail, HER2/neu, E-cadherin, Vimentin, α-SMA, CD34, Ki-67 and p63 was performed in 60 patients of different age with breast cancer. Native preparations were stained with picrofuchsin according to van Gieson Alcian blue. Inflammatory infiltrate cells were examined for antibodies CD45, CD3, CD4, CD8, CD20, CD68.Results. In ductal carcinoma, positive expression for estrogen and progesterone was found in 82.7% and 86.3%, respectively, the proliferation index ranged before 66,6 %, and p-53 was positive in 97%. In lobular cancer, positive expression to estrogen and progesterone was observed in 83.4% and 66.6%, respectively, the index of proliferative activity at the level of 50 %, and p-53 was positive in 66.6%. Positive moderate expression of HER-2/neu was determined in 47% of ductal and 50% of lobular cancers. Estrogen plays an important role in the development of invasive breast cancer, leads to tumor progression and contributes to EMT. EMT, in turn, leads to the expression of E-cadherin associated with a worse survival prognosis. EMT indirectly leads to the intensification of angiogenesis, and the presence of a large number of newly formed vessels increases the risk of metastasis. Histochemical methods were used to determine the growth of fibrous tissue around invasively growing cancer complexes. Cells located perifocally looked like fibroblasts, immunohistochemically moderately expressed Vimentin and weakly expressed pancytokeratin, which proved the tumor nature of the cells and the acquisition of mesenchymal features by them. The inflammatory infiltrate along the periphery of the tumor growth consisted mainly of T- and B-lymphocytes, and around the cancer complexes - of B-lymphocytes and macrophages.Conclusion. The study of the immunohistochemical tumor phenotype will make it possible to prescribe adequate polychemotherapy and determine the prognosis of the course of the disease.

TP53-related signature for predicting prognosis and tumor microenvironment characteristics in bladder cancer: A multi-omics study.

Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor-ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor-ligand pairs. Conclusion: BLCA patients with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA.

The significance of CD14 in clear cell renal cell carcinoma progression and survival prognosis

Purpose: CD14-positive tumour and immune cells have been implicated in cancer progression. This study evaluated the prognostic significance of CD14 immunostaining in clear cell renal cell carcinoma (ccRCC) compared to the adjacent non-cancer kidney, and serum soluble CD14 (sCD14) levels in patients versus controls. Methods: Immunohistochemistry was performed for CD14 on ccRCC and the corresponding adjacent non-cancer kidney tissue from 88 patients. Staining intensity was determined using Aperio ImageScope morphometry. Serum sCD14 was evaluated for 39 ccRCC patients and 38 non-cancer controls using ELISA. CD14 levels were compared with tumour characteristics and survival status. Results: CD14 overall and nuclear immunostaining was higher in ccRCC compared to the adjacent non-cancer kidney tissue. CD14 nuclear immunostaining in the adjacent non-cancer kidney was significantly associated with advanced stage and adverse RCC survival prognosis. Serum sCD14 concentration was elevated in ccRCC patients compared to non-cancer controls and was also significantly associated with tumour stage and worse survival prognosis. Higher CD14 expression, in particular CD14 positive immune cell infiltrates found in the adjacent non-RCC kidney tissue, were associated with tumour progression and poorer prognosis. Conclusion: The levels of CD14 in non-RCC adjacent kidney and serum could be potential prognostic indicators.

JNK pathway plays a critical role for expansion of human colorectal cancer in the context of BRG1 suppression.

Tumor stem cells (TSCs), capable of self‐renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c‐JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c‐JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC.

Identification of a Novel Pyroptosis-Related Gene Signature Indicative of Disease Prognosis and Treatment Response in Skin Cutaneous Melanoma.

PurposePyroptosis plays an important role in the occurrence and progression of many tumors; however, the specific mechanisms involved remain unknown. Here, we construct a pyroptosis-related gene signature that can be used to predict survival prognosis of skin cutaneous melanoma (SKCM) and provide guidance for clinical treatment.MethodsBy integrating data from the two databases from the GTEx and TCGA, differentially expressed genes (DEGs) from normal tissues and skin cutaneous tumor tissues were identified. The main signaling pathways and function enrichment of these differential genes were determined. Univariate and multivariate COX regression analysis, and risk score analysis were used to construct a signature to assess its predictive value for overall survival. The mRNA expression of these five genes in melanoma cells was determined by quantitative polymerase chain reaction (qPCR). The pRRophetic algorithm was used to estimate the half-maximal inhibitory concentration (IC50) of chemotherapy drugs in SKCM patients. The expression of multiple immune checkpoint genes also was evaluated.ResultsSixteen DEGs associated with pyroptosis in SKCM and normal skin tissues were identified. Of these, 12 pyroptosis-related DEGs were associated with the prognosis of SKCM. A five-gene signature (GSDMA, GSDMC, IL-18, NLRP6, and AIM2) model was constructed. Patients were divided into high-risk and low-risk groups using the risk scores. Of these, the high-risk group had a worse survival prognosis. There are significant differences in the predicted sensitivity of the high-risk and low-risk groups to chemotherapeutic drugs. In addition, compared with the high-risk group, the low-risk group showed higher expression of PD-1, PDL-1, CTLA-4, LAG-3, and VSIR.ConclusionIn this study, we constructed a novel prognostic pyroptosis-related gene-signature for SKCM. These genes showed good predictive value for patient prognosis and could provide guidance for better treatment of SKCM patients.

MiR-129-5p exerts Wnt signaling-dependent tumor-suppressive functions in hepatocellular carcinoma by directly targeting hepatoma-derived growth factor HDGF

BackgroundIn hepatocellular carcinoma (HCC), histone deacetylases (HDACs) are frequently overexpressed. This results in chromatin compaction and silencing of tumor-relevant genes and microRNAs. Modulation of microRNA expression is a potential treatment option for HCC. Therefore, we aimed to characterize the epigenetically regulated miR-129-5p regarding its functional effects and target genes to understand its relevance for HCC tumorigenesis.MethodsGlobal miRNA expression of HCC cell lines (HLE, HLF, Huh7, HepG2, Hep3B) and normal liver cell lines (THLE-2, THLE-3) was analyzed after HDAC inhibition by miRNA sequencing. An in vivo xenograft mouse model and in vitro assays were used to investigate tumor-relevant functional effects following miR-129-5p transfection of HCC cells. To validate hepatoma-derived growth factor (HDGF) as a direct target gene of miR-129-5p, luciferase reporter assays were performed. Survival data and HDGF expression were analyzed in public HCC datasets. After siRNA-mediated knockdown of HDGF, its cancer-related functions were examined.ResultsHDAC inhibition induced the expression of miR-129-5p. Transfection of miR-129-5p increased the apoptosis of HCC cells, decreased proliferation, migration and ERK signaling in vitro and inhibited tumor growth in vivo. Direct binding of miR-129-5p to the 3′UTR of HDGF via a noncanonical binding site was validated by luciferase reporter assays. HDGF knockdown reduced cell viability and migration and increased apoptosis in Wnt-inactive HCC cells. These in vitro results were in line with the analysis of public HCC datasets showing that HDGF overexpression correlated with a worse survival prognosis, primarily in Wnt-inactive HCCs.ConclusionsThis study provides detailed insights into the regulatory network of the tumor-suppressive, epigenetically regulated miR-129-5p in HCC. Our results reveal for the first time that the therapeutic application of mir-129-5p may have significant implications for the personalized treatment of patients with Wnt-inactive, advanced HCC by directly regulating HDGF. Therefore, miR-129-5p is a promising candidate for a microRNA replacement therapy to prevent HCC progression and tumor metastasis.

The endosomal pH regulator NHE9 is a driver of stemness in glioblastoma.

A small population of self-renewing stem cells initiate tumors and maintain therapeutic resistance in glioblastoma (GBM). Given the limited treatment options and dismal prognosis for this disease, there is urgent need to identify drivers of stem cells that could be druggable targets. Previous work showed that the endosomal pH regulator NHE9 is upregulated in GBM and correlates with worse survival prognosis. Here, we probed for aberrant signaling pathways in patient-derived GBM cells and found that NHE9 increases cell surface expression and phosphorylation of multiple receptor tyrosine kinases (RTKs) by promoting their escape from lysosomal degradation. Downstream of NHE9-mediated receptor activation, oncogenic signaling pathways converged on the JAK2-STAT3 transduction axis to induce pluripotency genes Oct4 and Nanog and suppress markers of glial differentiation. We used both genetic and chemical approaches to query the role of endosomal pH in GBM phenotypes. Loss-of-function mutations in NHE9 that failed to alkalinize endosomal lumen did not increase self-renewal capacity of gliomaspheres in vitro. However, monensin, a chemical mimetic of Na+/H+ exchanger activity, and the H+ pump inhibitor bafilomycin bypassed NHE9 to directly alkalinize the endosomal lumen resulting in stabilization of RTKs and induction of Oct4 and Nanog. Using orthotopic models of primary GBM cells we found that NHE9 increased tumor initiation in vivo. We propose that NHE9 initiates inside-out signaling from the endosomal lumen, distinct from the established effects of cytosolic and extracellular pH on tumorigenesis. Endosomal pH may be an attractive therapeutic target that diminishes stemness in GBM, agnostic of specific receptor subtype.

An Integrated Analysis of the Identified PRPF19 as an Onco-immunological Biomarker Encompassing the Tumor Microenvironment, Disease Progression, and Prognoses in Hepatocellular Carcinoma.

Background: Targeting the mRNA splicing process has been identified as a therapeutic strategy for human cancer. PRPF19 is an RNA binding protein that is involved in pre-mRNA processing and repairing DNA damage; the aberrant expression of PRPF19 is potentially associated with carcinogenesis. However, the biological role of PRPF19 in hepatocellular carcinoma (HCC) is still elusive. Methods: Data obtained from TCGA, Oncomine, and GEO were used to investigate the PRPF19 expression level and its role in tumor immune infiltration, prognosis, and the tumor progression of cohorts from HCC. Using various databases and tools (UALCAN, TIMER, TISMO, and PathCards), we presented the potential mechanisms of PFPF19 upregulation, PRPF19-related pathways, and its biological functions in liver cancer. Results: For HCC, PRPF19 expression was found upregulated both in single tumor cells and tissues. Furthermore, the increased expression of PRPF19 was significantly correlated to clinical characteristics: advanced stage, vascular invasion, high AFP, and poor prognosis of HCC. According to the tumor-immunological analysis, we found that PRPF19 is positively correlated with infiltrating myeloid-derived suppressor cells (MDSCs). Moreover, the microenvironment of HCC tissues with high expression of PRPF19 is highly immunosuppressive (lower T-lymphocytes, multiple immune checkpoints upregulated). Patients with high expression of PRPF19 and high MDSCs had a worse survival prognosis as well. TP53 mutation may have a positive effect on PRPF19 expression via decreased promoter methylation of PRPF19. By TF-mRNA network analysis, key transcription factors (TFs) in TC-NER and PCS pathways (PRPF19 involved) were identified. Conclusion: This work implied that PRPF19 is associated with tumor immune evasion and progression, and serves as a prognostic marker for worse clinical outcomes with HCC. Thus, this critical regulator could serve as a potential therapeutic target of HCC.

Comprehensive Analysis of the Glycolysis-Related Gene Prognostic Signature and Immune Infiltration in Endometrial Cancer.

Glucose metabolic reprogramming and immune imbalance play important roles in the progression of cancers. The purpose of this study is to develop a glycolysis-related prognostic signature for endometrial cancer (EC) and analyze its relationship with immune function. The mRNA expression profiling of the glycolysis-related genes and clinical data of EC patients were downloaded from The Cancer Genome Atlas (TCGA). We identified a glycolysis-related gene prognostic signature for predicting the prognosis of EC by using The Least Absolute Shrinkage and Selection Operator (LASSO) regression and found the patients in the high-risk group had worse survival prognosis. Multivariate Cox regression analysis showed that the gene signature was an independent prognostic factor for EC. The ROC curve confirmed the accuracy of the prognostic signature (AUC = 0.730). Then, we constructed a nomogram to predict the 1–5 years survival rate of EC patients. The association between the gene signature and immune function was analyzed based on the “ESTIMATE” and “CIBERSORT” algorithm, which showed the immune and ESTIMATE scores of patients in the high-risk group were lower, while the low immune and ESTIMATE scores were associated with a worse prognosis of patients. The imbalance of immune cells was also found in the high-risk group. Further, the protein of CDK1, a gene in the signature, was found to be closely related to prognosis of EC and inhibition of CDK1 could inhibit migration and promote apoptosis of EC cells. This study reveals a link between glycolysis-related gene signature and immunity, and provides personalized therapeutic targets for EC.